The lack of an efficient, rapid preclinical imaging modality for non-invasive detection and longitudinal tracking of early stage metastatic cancer in whole animals has been a significant hindrance to drug discovery studies. Current studies of novel drug delivery and metastasis treatment strategies require large cohorts of serially sacrificed animals. Optical molecular imaging offers great promise as a longitudinal imaging technique for preclinical cancer research. The unique advantage of optical imaging over radiological modalities is the capability for lifetime and spectral labelling to track multiple physiological components of disease simultaneously (multiplexing). Fluorescence lifetime contrast using time domain (TD) detection also enables the efficient removal of tissue autofluorescence, a major impediment for whole body optical imaging. We have demonstrated that lifetime contrast with time domain (TD) optical detection provides a more than 20-fold sensitivity increase over traditional continuous wave (CW) fluorescence imaging for detecting iRFP-labeled cancer cells dispersed in the mouse lung. These results demonstrate the high potential of TD imaging for monitoring metastasis in whole mice at earlier stages than currently possible. Motivated by our progress and the potential impact of the technology for preclinical cancer imaging, our goal in this academic industry partnership is to integrate time domain technology into a commercially established preclinical imaging system from PerkinElmer, a leading provider of in vivo imaging systems and reagents. MGH and PerkinElmer will partner to develop a robust prototype time domain preclinical optical tomography platform and validate the system using small animal tumor models. The system will also incorporate micro-CT imaging for anatomical co-registration and to aid the optical tomography algorithms. The system will be designed to meet performance criteria for commercial use. The proposed imaging platform will provide several new benefits to existing commercial imaging platforms from PKI, including 1) more than 20-fold improvement in sensitivity using autofluorescence removal, allowing the detection of metastasis earlier than currently possible; (2) lifetime multiplexing to visualize multiple fluorophores simultaneously in a single animal; (3) improved resolution over CW using early photon detection; (4) accurate and fast 3D fluorescence reconstructions using accelerated Monte Carlo software. These features will add to the existing capability of PerkinElmer's systems for bioluminescence, multispectral fluorescence and CT imaging, to deliver the most versatile preclinical optical imaging platform commercially available. .